Diabetic retinopathy (DR) is the most common complication in patients with diabetes. Diabetic macular edema (DME) can occur in any stage of DR and is the main cause of vision loss in patients with DR. The incidence of DME after 10 years of follow-up has been reported to be 20.1% in Type 1 diabetes, 25.4% in Type 2 insulin-dependent diabetes, and 13.9% in Type 2 non-insulin-dependent diabetes (Klein et al. (1995) Ophthalmology 102, 7-16). The ETDRS trial ((1985) Photocoagulation for Diabetic Macular Edema—Early Treatment Diabetic-Retinopathy Study Report. 1. Archives of Ophthalmology 103, 1796-1806), a pioneering study in DR, demonstrated that although laser photocoagulation therapy reduces the risk of moderate visual loss in DME eyes by ˜50% at 3 years, only a few eyes gain vision, and some eyes continue to experience vision loss even after intensive treatment. In recent years, advances in pharmacotherapy and ocular drug delivery have shown promise in the treatment of DME. The RESTORE study, one of two pivotal Phase III trials in DME (Mitchell et al. (2011) Ophthalmology 118, 615-625) demonstrated that Lucentis® was superior to laser monotherapy. The mean change in best-corrected visual acuity (BCVA), which was the primary clinical endpoint, was significantly improved in the Lucentis® group (+6.1 letters for the Lucentis® group vs. +0.8 letters for the laser group; p<0.0001). Similar beneficial effects have been demonstrated with VEGF Trap-Eye (Regeneron Inc. NY, USA) and Ozurdex® (dexamethasone intravitreal implant; Allergan Inc., CA, USA)(Do et al. (2011) Ophthalmology 118, 1819-1826; Haller et al. (2010) Archives of Ophthalmology 128, 289-296). However, 16% of Ozurdex treated eyes developed increased intra-ocular pressure, a risk for glaucoma.
Despite these new treatment options for DME, there remains a substantial unmet medical need. ˜25% of eyes in the Lucentis® pivotal trials did not gain any visual acuity after 12 months of treatment and ˜50% of eyes are left with visual acuity of 20/40 or worse. Genome-wide association studies indicated that diabetics who are homozygous for an erythropoietin (Epo) promoter polymorphism (T) have a 2.17-fold higher risk of developing proliferative DR (Tong et al. (2008) Proc. Natl. Acad. Sci. U.S.A 105, 6998-7003). Interestingly, people with the T promoter allele for Epo have approximately 7.5-fold higher vitreal concentration of Epo compared to people with the G allele (Tong et al. (2008) Proc. Natl. Acad. Sci. U.S.A 105, 6998-7003).
There remains a need to develop an effective treatment for diabetic retinopathy, particularly DME to replace or supplement current treatments.